Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial

Summary

Background

New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population.

Methods

In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3–4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of “clear” or “almost clear” (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591.

Findings

Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events.

Intepretation

In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis.

Funding

Pfizer Inc.

Introduction

Moderate-to-severe plaque psoriasis is a chronic, immune-mediated, systemic disease that affects patients both physically and psychologically, leading to major quality-of-life impairment.¹ Interplay between the innate and adaptive immune systems and epidermal proliferation and differentiation underlie the disease pathogenesis, causing sustained inflammation and epidermal hyperplasia, which ultimately results in the formation and persistence of psoriatic lesions.2, 3, 4 Patients with moderate-to-severe plaque psoriasis need treatment with phototherapy or systemic agents. However, long-term exposure to phototherapy could be associated with an increased risk of skin cancers,5, 6 whereas prolonged use of classical systemic treatments (methotrexate, ciclosporin, and acitretin) is associated with organ toxicity (liver, kidney, and mucocutaneous toxicity, respectively) that limits their long-term usefulness.7, 8, 9, 10, 11

Despite the availability of biological therapies, including tumour necrosis factor inhibitors and interleukin 12 or interleukin 23 inhibitors,8, 10, 11, 12 patients with psoriasis who have extensive or severe disease still need new treatment options, because loss of treatment efficacy over time, immunogenicity, adverse events, and the need for parenteral administration can compromise the long-term usefulness of biologicals in some cases and have been cited by patients as reasons contributing to treatment discontinuation.13, 14, 15, 16 Furthermore, 20–50% of patients do not achieve or lose satisfactory clinical responses to biologicals in the short-to-medium term, which leads to poor drug continuation rates and substantial patient dissatisfaction.14, 16, 17, 18 Similarly, new, effective, well-tolerated, and convenient treatments with new mechanisms of action that address these latter problems are needed to achieve adequate clinical responses and provide patients and physicians with a broader range of therapies to reduce the psoriasis disease burden.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) intracellular signalling pathway is used by many cytokines and is implicated in the pathogenesis of chronic immune-mediated and inflammatory diseases including psoriasis.¹⁹ Tofacitinib is an oral JAK inhibitor that mainly interferes with JAK1 and JAK3 signalling and has previously shown significantly better efficacy than placebo in a 12-week phase 2b dose-ranging study in patients with moderate-to-severe plaque psoriasis.²⁰

We report the results of the first phase 3 study comparing the efficacy and safety of two doses of tofacitinib (5 mg and 10 mg twice daily) versus etanercept 50 mg subcutaneously twice weekly or placebo for the treatment of moderate-to-severe chronic plaque psoriasis in patients who are candidates for systemic therapy or phototherapy. The 5 mg and 10 mg twice daily doses of tofacitinib were selected to offer the best balance of safety and efficacy based on the phase 2b study results,20, 21 whereas the 50 mg twice weekly dose of etanercept is the highest approved dose for psoriasis treatment that also has a favourable safety profile.⁹